Cellular ABCs of rigidity sensing
Cells are the smallest structural and functional units in any organism. Their sensing capacity helps them cope with dynamic conditions and maintain normal health. Aberrant rigidity sensing in cancerous cells enables them to grow on soft matrices unlike normal cells that are dependent on extracellular matrix (ECM) rigidity. Under the aegis of the RIGIDITY SENSING (Mechanisms of cellular rigidity sensing) project, researchers are elucidating how the cells can sense ECM rigidity through the study of cell-ECM adhesions and force production. Under consideration are key factors involved in adhesion such as transmembrane integrin molecules (e.g. RGD (Arg-Gly-Asp)) in fibronectin and the molecular basis of force production. Project members achieved significant progress during the first two years of the project. They explored different techniques to functionalise gold nanodots for accurate attachment of RGD ligands to facilitate cell adhesion. Such nanofabricated surfaces are necessary to study protein recruitment during cell-ECM adhesion and understand the rigidity sensing mechanism. Due to limited success with passivation of such surfaces using polyethylene glycol, researchers are currently exploring the utility of lipid bilayers. Studies on force production mechanisms using arrays of elastic polydimethylsiloxane (PDMS) pillars proved to be more fruitful. They were able to study the recruitment of proteins to the PDMS pillars during force production via live cell microscopy and super-resolution analysis. They also performed experiments where they knocked down expression of selected proteins to determine their role in force regulation and rigidity sensing. Researchers successfully identified important factors involved in sensing ECM rigidity. Knocking down expression of α-actinin or tropomyosin-1 affected the cells' ability to accurately sense ECM rigidity. As a result, non-transformed breast epithelial cells were able to grow on very soft surfaces. Aggressive tumours have been linked to aberrant sensing mechanisms as well as downregulated tropomyosin-1 levels. Besides an enhanced knowledge base, project findings could be used to develop novel personalised anticancer treatment strategies for patients with low tropomyosin-1 levels.
